EP0181675B1 - Procédé de préparation de L-alpha-amino-acide et D-alpha-amino-acide-amide - Google Patents

Procédé de préparation de L-alpha-amino-acide et D-alpha-amino-acide-amide Download PDF

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Publication number
EP0181675B1
EP0181675B1 EP85201842A EP85201842A EP0181675B1 EP 0181675 B1 EP0181675 B1 EP 0181675B1 EP 85201842 A EP85201842 A EP 85201842A EP 85201842 A EP85201842 A EP 85201842A EP 0181675 B1 EP0181675 B1 EP 0181675B1
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EP
European Patent Office
Prior art keywords
amino acid
amino
acid amide
potassium
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP85201842A
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German (de)
English (en)
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EP0181675A1 (fr
Inventor
Pieter Laurens Kerkhoffs
Wilhelmus Hubertus Joseph Boesten
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Stamicarbon BV
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Stamicarbon BV
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Priority to AT85201842T priority Critical patent/ATE45982T1/de
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/78—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
    • C12N9/80—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5) acting on amide bonds in linear amides (3.5.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids

Definitions

  • the invention relates to a process for the preparation of L-a-amino acid and D-a-amino acid amide from DL-a-amino acid made by contacting the DL-a-amino acid amide in an aqueous solution with an a-amino acyl amidase containing preparation obtained from a culture of Pseudomonas putida in the presence of traces of bivalent metal ions as activator.
  • a process is known from US patent 4,080,259.
  • magnesium, manganese and zinc compounds are mentioned as activator for the a-amino acyl amidase activity (also referred to as amino peptidase activity) of preparations obtained from microorganisms of the Pseudomonas genus.
  • leucine-amino peptidase the activity of which in fact corresponds with that of the subject-a-amino acyl peptidase
  • Other enzymes may be activated by bivalent metal ions, vide for instance SRI report No. 139, pp. 181-2 (1981).
  • the reference solution for the invention therefore is an a-amino acyl amidase containing aqueous solution of pure DL-a-amino acid amide in which traces of bivalent metal ions are present as activator.
  • the dry enzyme preparations already contain such trace elements, for as a rule they are added in the fermentor, where the micro-organism is cultivated. After cultivation, the trace elements automatically end up in an, optionally dried, enzyme preparation.
  • a customary synthesis for DL-a-amino acid proceeds via the so-called Strecker synthesis, in which an aldehyde is coupled to a cyanide and an ammonium salt, yielding a DL-a-amino nitrile.
  • the DL-a-amino nitrile thus obtained can subsequently be treated with a ketone in a strongly basic medium, upon which the DL-a-amino acid amide is formed.
  • This amino nitrile conversion is described in British patent specification 1 548 032.
  • Another possible way of converting DL-a-amino nitrile into the corresponding DL-a-amino acid amide is by treating it with concentrated sulphuric acid, followed by neutralization with a hydroxide.
  • a-amino acyl amidase preparation obtained from a culture of Pseudomonas putida is at least in part inhibited (relative to the reference solution) by sodium ions.
  • sodium ions may, for instance, originate from sodium cyanide, used in the Strecker synthesis, and/or from sodium hydroxide, used in the conversion of DL-a-amino nitrile.
  • sodium ions' presence in the solution are conceivable, but actually it is irrelevant how these ions have entered the solution. So far, sodium ions had not been known to have such an inhibitory effect on a-amino acyl amidase preparations of Pseudomonas putida.
  • the object of the invention is to provide a solution for the disadvantageous effects of inhibition, with which applicant was confronted when carrying out the process as described in the preamble.
  • a further object of the invention is to provide a process as described in the preamble in which the enzyme activity is even increased relative to the reference solution.
  • the process according to the invention for the preparation of L-a-amino acid and D-a-amino acid amide from DL-a-amino acid amide by contacting the DL-a-amino acid amide in an aqueous solution with an a-amido acyl amidase containing preparation obtained from a Pseudomonas putida culture in the presence of traces of bivalent metal ions as activator is characterized in that the aqueous solution also contains a potassium salt chosen from the group consisting of potassium sulphate and potassium chloride.
  • the process according to the invention of course is not restricted to the practical embodiment as described above, but in general comprises the enzymic separation of DL-a-amino acid amides in an aqueous solution.
  • This aqueous solution is prepared is less important.
  • potassium per litre of aqueous solution 0.1-3 moles potassium can be applied as sulphate or as chloride.
  • the process according to the invention in principle relates to a-amino acyl amidase containing preparations from the Pseudomonas putida strain as well as from mutants thereof.
  • a highly suitable Pseudomonas putida strain is registered under number 12633 in the American Type Culture Collection at Washington D.C., United States of America.
  • a preparation having a-amino acyl amidase activity can be obtained by precipitation of the cells of Pseudomonas putida, optionally use being made of a flocculating agent.
  • the cells can also be crosslinked or they can be bonded to or absorbed on a carrier.
  • it may be desirable to modify the cell walls for instance by a heat treatment or by chemical treatment (for instance with toluene), to make the enzyme better accessible.
  • a crude preparation can also be obtained by destroying the cell walls and recovering the enzyme by extraction, filtration and optionally by spray drying.
  • a preparation consisting of the pure enzyme can be obtained in conventional manner from the crude product referred to above. Crude or pure enzyme preparations can also be immobilized on a carrier, as can entire cells.
  • the preparation having a-amino acyl amidase activity is contacted with the DL-a-amino acid amide in an aqueous medium at a temperature of between 0 and 60°C, and by preference at a temperature of between 0 and 40°C, and at a pH of between 6 and 10.5, and by preference of between 7.5 and 9.5.
  • the weight ratio of the (unpurified) enzyme preparation to the substrate may vary widely, for instance between 1:25 and 1:750. If a pure enzyme is used, a higher ratio can be applied.
  • the free acid can be separated from the remaining D-a-amino acid amide and the latter compound can subsequently also be hydrolyzed, yielding D-a-amino acid.
  • the D-a-amino acid amide can be dissolved together with the L-a-amino acid (as is the case with D-phenyl glycine amide and D-valine amide), the D-a-amino acid can be obtained in the following way.
  • an aldehyde for instance benzaldehyde
  • benzaldehyde is added in an amount that is equimolar or higher relative to the D-a-amimo acid amide, resulting in formation of an insoluble Schiff base of the D-a-amino acid amide (D-N-benzylidene compound of D-a-amino acid amide).
  • the Schiff base can, after separation, subsequently be hydrolyzed to the D-a-amino acid using a strong acid.
  • the process according to the invention is suitable for isolating optically active natural or synthetic-amino acids and/or D-a-amino acid amides, such as the D and/or L form of phenylalanine, 3,4 - dihydroxyphenylalanine, homophenylalanine, tyrosine, methionine, valine, leucine, alanine, phenylglycine, 4 - hydroxyphenylglycine, 4 - alkoxyphenylglycine and other substituted phenylglycines.
  • the essence of the process according to the invention is that the enzyme can be activated, independently of the substrate.
  • a preferred practical embodiment of the preparation of an L-a-amino acid and a D-a-amino acid amide, starting from an aldehyde, cyanide and ammonium salt, which also comprises the process according to the invention, is as follows:
  • An aldehyde RCHO where R represents an alkyl or aryl group, substituted or not, is introduced into an aqueous ammonia solution, in which potassium cyanide and ammonium sulphate have also been dissolved.
  • the solution is heated at 40°C during 1-4 hours. This results in formation of DL-a-amino nitrile (plus potassium sulphate).
  • a ketone is added, as well as potassium hydroxide, and DL-a-amino acid amide is formed.
  • a high-activity enzymic separation can be effected by addition of an a-amino acyl amidase preparation from Pseudomonas putida.
  • the D-a-amino acid amide can be worked up further to the corresponding D-a-amino acid via Schiff base formation.
  • the DL-a-valineamide yield was determined. The value found was 88.4%, calculated on the basis of butyraldehyde.
  • the pH of the solution was 9.5. After removal of the potassium sulphate by filtration, the solution was given a temperature of 40°C and subsequently 15 g of an a-amino acyl amidase containing preparation, obtained from a culture of Pseudomonas putida ATCC 12633, was added. After this, stirring was applied for 20 hours at 40°C.
  • the precipitated D-N-benzylidenevalineamide was filtered off, washed with 4x25 ml water on the filter and dried for 16 hours at 45°C and 16 mbar. (From the filtrate L-valine can be recovered, if desired).
  • the yield of dry and pure (determined by thin-layer chromatography) D-N-benzylidenevalineamide was 82.6 g. Relative to isobutyraldehyde the efficiency was 40.5%, and relative to valineamide 91.6%.
  • the D-valine was filtered off and washed on the filter with 3x25 ml water and 3x25 ml acetone and then dried for 16 hours at 45°C and 16 mbar.
  • the yield of pure (determined by thin layer chromatography) and sulphate-free D-valine was 35.4 g.
  • the overall efficiency was 30.3, calculated relative to isobutyraldehyde (it should, however, be noted that in theory only 0.5 mole D-valine can be prepared from 1 mole isobutyraldehyde).

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)

Claims (6)

1. Procédé de préparation de L-alpha-amino-acide et de l'amide de D-alpha-amino-acide à partir de l'amide de DL-alpha-amino-acide par la mise en contact de l'amide de DL-alpha-amino-acide en solution aqueuse avec une composition contenant une alpha-amino-acyl-amidase qu'on obtient à partir d'une culture de Pseudomonas putida en présence de traces d'ions de métaux divalents à titre d'activant, caractérisé en ce que la solution aqueuse contient également un sel de potassium choisi parmi le sulfate de potassium et le chlorure de potassium.
2. Procédé selon la revendication 1, caractérisé en ce que la solution aqueuse contient de 0,1 à 3 moles d'ion potassium par litre.
3. Procédé selon la revendication 1 ou 2, caractérisé en ce que l'ion potassium est présent sous forme de sulfate de potassium.
4. Procédé selon l'une quelconque des revendications 1 à 3, caractérisé en ce qu'on utilise une composition d'alpha-amino-acylamidase provenant de Pseudomonas putida ATCC 12633.
5. Procédé selon l'une quelconque des revendications 1 à 4, caractérisé en ce qu'on applique le DL-phénylgycineamide ou le DL-valine-amide sous forme d'amide de DL-alpha-amino-acide.
6. Procédé selon la revendication 1, dans lequel on prépare l'amide de DL-alpha-aminoacide en convertissant d'abord un aldéhyde en un DL-alpha-amino-nitrile en solution aqueuse avec du cyanure de potassium et du sulfate d'ammonium, puis on hydrolyse le DL-alpha-amino-nitrile en amide de DL-alpha-amino-acide, caractérisé en ce que la solution aqueuse contient des ions potassium et des ions sulfate qui restent à partir de la préparation initiale de nitrile.
EP85201842A 1984-11-15 1985-11-11 Procédé de préparation de L-alpha-amino-acide et D-alpha-amino-acide-amide Expired EP0181675B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT85201842T ATE45982T1 (de) 1984-11-15 1985-11-11 Verfahren zur herstellung von l-alpha-aminosaeure und d-alpha-aminosaeureamid.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NL8403487 1984-11-15
NL8403487A NL8403487A (nl) 1984-11-15 1984-11-15 Werkwijze voor de enzymatische scheiding van dl-alfa-aminozuuramides.

Publications (2)

Publication Number Publication Date
EP0181675A1 EP0181675A1 (fr) 1986-05-21
EP0181675B1 true EP0181675B1 (fr) 1989-08-30

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ID=19844770

Family Applications (1)

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EP85201842A Expired EP0181675B1 (fr) 1984-11-15 1985-11-11 Procédé de préparation de L-alpha-amino-acide et D-alpha-amino-acide-amide

Country Status (12)

Country Link
US (1) US4880737A (fr)
EP (1) EP0181675B1 (fr)
JP (1) JPS61119199A (fr)
AT (1) ATE45982T1 (fr)
BR (1) BR8505749A (fr)
CA (1) CA1258244A (fr)
DE (1) DE3572691D1 (fr)
DK (1) DK161337C (fr)
ES (1) ES8701150A1 (fr)
IL (1) IL77054A0 (fr)
NL (1) NL8403487A (fr)
PT (1) PT81475B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0334358A2 (fr) * 1988-03-24 1989-09-27 Kyowa Hakko Kogyo Co., Ltd. D-amidase et procédé de production de D-alpha-alanine et/ou L-alpha-alanine amide
EP0383403A1 (fr) * 1989-02-16 1990-08-22 Stamicarbon B.V. Procédé de préparation de produits chimiques organiques
US5252470A (en) * 1988-03-24 1993-10-12 Kyowa Hakko Kogyo Co., Ltd. D-amidase and process for producing D-α-alanine and/or L-α-alanineamide
EP0735143A1 (fr) * 1995-03-28 1996-10-02 Tanabe Seiyaku Co., Ltd. Procédé pour la préparation des acides D-aminés
US6166227A (en) * 1998-07-15 2000-12-26 Bristol-Myers Squibb Co. Preparation of (S)-2-amino-6, 6-dimethoxyhexanoic acid methyl ester via novel dioxolanes

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3816063A1 (de) * 1988-05-06 1989-11-23 Schering Ag Verfahren zur herstellung von l-aminosaeuren und aminosaeure-amiden
US5593871A (en) * 1990-09-20 1997-01-14 E. I. Du Pont De Nemours And Company Process for the preparation of enantiometric 2-alkanoic acid amides from nitriles
JP3263791B2 (ja) * 1992-09-30 2002-03-11 ソニー株式会社 Ｙｃ分離回路
US6214604B1 (en) * 1995-05-08 2001-04-10 Lonza Ag Biotechnical production process of piperazine R-α-carboxylic acids and piperazine S-α-carboxylic acid amide
US6248551B1 (en) * 1997-03-28 2001-06-19 Institut Pasteur Helicobacter aliphatic amidase AmiE polypeptides, and DNA sequences encoding those polypeptides
CN113025536B (zh) * 2021-04-28 2022-11-25 桂林理工大学 一株假单胞菌pr1及其制备方法和应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL181508C (nl) * 1974-06-14 1987-09-01 Stamicarbon Werkwijze voor de bereiding van een d-aminozuuramide en een l-aminozuur en werkwijze voor de bereiding van d-fenylglycine.
NL182954C (nl) * 1975-08-20 1988-06-16 Stamicarbon Werkwijze voor het bereiden van alfa-aminozuuramide.
LU74142A1 (fr) * 1976-01-08 1977-07-22
FR2372797A1 (fr) * 1976-12-03 1978-06-30 Anvar Procede d'hydrolyse catalytique chimique d'a-amino-nitriles ou de leurs sels
DE3168967D1 (en) * 1980-12-02 1985-03-28 Health Lab Service Board Production of aryl acylamidases

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0334358A2 (fr) * 1988-03-24 1989-09-27 Kyowa Hakko Kogyo Co., Ltd. D-amidase et procédé de production de D-alpha-alanine et/ou L-alpha-alanine amide
EP0334358A3 (en) * 1988-03-24 1989-11-29 Kyowa Hakko Kogyo Co., Ltd. Novel d-amidase and process for producing d-alpha-alanine and/or l-alpha-alanineamide
US5130240A (en) * 1988-03-24 1992-07-14 Kyowa Hakko Kogyo Co., Ltd. Process for producing d-alpha-alanine and/or l-alpha-alanineamide by arthrobacter sp
US5252470A (en) * 1988-03-24 1993-10-12 Kyowa Hakko Kogyo Co., Ltd. D-amidase and process for producing D-α-alanine and/or L-α-alanineamide
EP0383403A1 (fr) * 1989-02-16 1990-08-22 Stamicarbon B.V. Procédé de préparation de produits chimiques organiques
EP0735143A1 (fr) * 1995-03-28 1996-10-02 Tanabe Seiyaku Co., Ltd. Procédé pour la préparation des acides D-aminés
US5783427A (en) * 1995-03-28 1998-07-21 Tanabe Seiyaku Co., Ltd. Process for preparing D-amino acids
US6166227A (en) * 1998-07-15 2000-12-26 Bristol-Myers Squibb Co. Preparation of (S)-2-amino-6, 6-dimethoxyhexanoic acid methyl ester via novel dioxolanes
US6248882B1 (en) 1998-07-15 2001-06-19 Bristol-Myers Squibb Co. Preparation of (s)-2-amino-6,6-dimethoxyhexanoic acid methyl ester via novel dioxolanes
US6329542B1 (en) 1998-07-15 2001-12-11 Bristol-Myers Squibb Co. Preparation of (S)-2-amino-6,6-dimethoxyhexanoic acid methyl ester via novel dioxolanes

Also Published As

Publication number Publication date
DK526385A (da) 1986-05-16
ATE45982T1 (de) 1989-09-15
US4880737A (en) 1989-11-14
NL8403487A (nl) 1986-06-02
DE3572691D1 (en) 1989-10-05
IL77054A0 (en) 1986-04-29
ES548864A0 (es) 1986-11-16
JPS61119199A (ja) 1986-06-06
PT81475B (en) 1987-04-07
PT81475A (en) 1985-12-01
BR8505749A (pt) 1986-08-12
DK161337B (da) 1991-06-24
CA1258244A (fr) 1989-08-08
ES8701150A1 (es) 1986-11-16
EP0181675A1 (fr) 1986-05-21
DK526385D0 (da) 1985-11-14
DK161337C (da) 1991-12-09

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